Mechanism of adenosine‐induced airways obstruction in allergic guinea pigs

Abstract

1 Inhaled adenosine induces airway obstruction in asthmatic but not healthy subjects, a phenomenon that is also observed in various animal species when they are immunised to a relevant antigen, but which does not occur in naı¨ve animals. The purpose of this study was to investigate the mechanisms of airway responsiveness to adenosine receptor agonists in anaesthetised allergic guinea pigs. 2 Inhaled adenosine 5 0 -monophosphate (AMP), the A 1 -selective adenosine receptor agonist N 6 -cyclopentyladenosine (CPA) and ovalbumin all caused airway obstruction in allergic guinea pigs, but not naı¨ve animals, as assessed by changes in total lung resistance. In contrast, the A 2a -selective (CGS 21680; 2-p-(2-carboxyethyl)phenethylamino-5 0 -N-ethylcarboxoamido adenosine) and A 3 -selective (IB-adenosine receptor agonists failed to elicit airway obstruction in passively sensitised guinea pigs. 3 Airway obstruction induced by AMP or CPA was not inhibited by the H 1 receptor antagonist, mepyramine (1 mg kg À1 ) in passively sensitised guinea-pigs. In contrast, airway obstruction to ovalbumin was significantly inhibited by this antagonist. 4 Airway obstruction induced by AMP and CPA was significantly inhibited in sensitised animals chronically treated with capsaicin. In contrast, airway obstruction to ovalbumin was not inhibited by this treatment. 5 Airway obstruction induced by AMP, CPA and ovalbumin was significantly inhibited following bilateral vagotomy or pharmacological treatment with atropine (2 mg kg À1 ). 6 Airway obstruction to CPA was inhibited by the adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.1-1 mg kg À1 ). In contrast, airway obstruction to ovalbumin was not inhibited by this treatment. 7 These observations provide evidence indicating that AMP and CPA may induce airway obstruction in sensitised guinea pigs by a mechanism unrelated to histamine release from mast cells, but is mediated via an adenosine A 1 -receptor-dependent mechanism. The inhibition of AMP-and CPA-induced airway obstruction by atropine, capsaicin and bilateral vagotomy suggests a neuronaldependent mechanism with the particular involvement of capsaicin-sensitive nerves.

Effect of a Specific and Selective A2BAdenosine Receptor Antagonist on Adenosine Agonist AMP and Allergen-Induced Airway Responsiveness and Cellular Influx in a Mouse Model of Asthma

“…The effect of NECA is partially blocked by enprofylline, a relative selective A 2B antagonist, or MRS 1523, a selective A 3 antagonist. In allergic guinea pig model, it was reported that A 1 agonist CPA induces airway obstruction by a neuronal-dependent mechanism, whereas A 2A agonist CGS-21680 or A 3 agonist IB-MECA has no effect (Keir et al, 2006). Interestingly, it was also reported that A 3 agonist IB-MECA could contract sensitized guinea pig trachea (Martin and Broadley, 2002).…”

Purinergic Signaling in the Airways

“…Mast cells were claimed to be activated after adenosine challenge in allergic, but not nonallergic, patients with asthma (Bochenek et al, 2008). AMP and an A 1 receptor-selective agonist induced airway obstruction in sensitized guinea pigs by a mechanism unrelated to release of histamine from mast cells but probably through stimulation of sensory nerves and reflex activity (Keir et al, 2006). A 3 receptor signaling contributed to airway mucin secretion after allergen challenge in mice (Young et al, 2006).…”

Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells

“…In addition, although A 1 receptors have also been shown to partially mediate adenosine-induced bronchoconstriction through a mast cell-independent pathway, targeting the A 1 receptor gene in human beings with asthma has been largely ineffective. 16,19,33,34 These observations suggest that endogenous adenosine may affect airway pathophysiology in ways other than eliciting bronchoconstriction. In this study, we have discovered that adensosine produces AHR in mice.…”